Lung Cancer Master Protocol Activation Announcement Jeff Allen, PhD - - PowerPoint PPT Presentation

Lung Cancer Master Protocol Activation Announcement

Jeff Allen, PhD Friends of Cancer Research

Panelists

• Jeff Allen, PhD, Friends of Cancer Research
• Roy Herbst, MD, PhD, Yale Cancer Center
• David Gandara, MD, UC Davis Cancer Center
• Vali Papadimitrakopoulou, MD, MD Anderson Cancer Center
• Ann Ashby, MBA, Foundation for the NIH
• Vince Miller, MD, Foundation Medicine
• Jeff Abrams, MD, Clinical Investigations Branch, NCI
• Janet Woodcock, MD, CDER, FDA
• Mary Redman, PhD, Fred Hutchinson Cancer Center

Roy Herbst, MD, PhD Yale Cancer Center

Governance Structure: S1400 Master Lung-1 Project

Multi-Sector Oversight Committee

Name Affiliation Roy Herbst (co-chair) Yale Cancer Center Ellen Sigal (co-chair) Friends of Cancer Research Jeff Abrams NCI Jeff Allen Friends of Cancer Research David Chang Amgen Andrea Ferris LUNGevity David Gandara UC Davis Cancer Center Rich Gaynor Eli Lilly Fred Hirsch University of Colorado Cancer Center Pasi Janne Dana Farber Cancer Institute Vali Papadimitrakopoulou MD Anderson Cancer Center Eric Rubin Merck Regina Vidaver National Lung Cancer Partnership Jack Welch NCI Janet Woodcock CDER, FDA Steven Young Addario Lung Cancer Medical Institute (ALCMI)

Drug Selection Committee

• Jeff Allen, Friends of Cancer Research
• Matt Hawryluk, Foundation Medicine
• Pat Keegan, FDA
• Liz Mansfield, FDA
• Shakun Malik, FDA
• Vince Miller, Foundation Medicine
• Mary Redman, Fred Hutchinson Cancer Center
• Ellen Sigal, Friends of Cancer Research
• Caroline Sigman, CCS Associates
• David Wholley, FNIH
• Roman Yelensky, Foundation Medicine

VOTING Members

Non- Voting Members

Roy Herbst (chair), Yale Cancer Center Gary Kelloff, NCI Kathy Albain, Loyola Medicine Vali Papadimitrakopoulou, MD Anderson Jeff Bradley, Washington University in St. Louis Suresh Ramalingam, Emory Healthcare Kapil Dhingra, KAPital Consulting David Rimm, Yale Cancer Center Gwen Fyfe, Consultant Mark Socinski, UPMC Cancer Center David Gandara, UC Davis Cancer Center Naoko Takebe, NCI Glenwood Goss, University of Ottawa Everett Vokes, University of Chicago Fred Hirsch, University of Colorado Cancer Center Jack Welch, NCI Peter Ho, QI Oncology Ignacio Wistuba, MD Anderson Pasi Janne, Dana Farber Cancer Institute Jamie Zwiebel, NCI Jeff Allen, Friends of Cancer Research Mary Redman, Fred Hutchinson Cancer Center Matt Hawryluk, Foundation Medicine Ellen Sigal, Friends of Cancer Research Shakun Malik, FDA David Wholley, FNIH Vince Miller, Foundation Medicine Roman Yelensky, Foundation Medicine

Non-Voting Members

David Gandara, MD University of California Davis Comprehensive Cancer Center

David R. Gandara, MD University of California Davis Comprehensive Cancer Center

Master Lung Protocol (S1400): Addressing unmet needs in NSCLC

“Strategies for Integrating Biomarkers into Clinical Development of New Therapies for Lung Cancer”

A Joint NCI Thoracic Malignancies Steering Committee-FDA Workshop Bethesda MD – February 2-3, 2012

• Trial Design Challenges in the Era of Biomarker-driven Trials
• Innovative Statistical Designs
• Challenges for Community Oncology Practice participation
• The Patient Perspective
• Drug & Biomarker Co-Development in Lung Cancer
• Failure of “All Comer” designs for drug development in NSCLC
• Need for Early Co-Development of drugs & associated biomarkers
• Development of Future Lung Cancer Clinical Trials
• TMSC Master Protocol Task Force in NSCLC
• Biomarker-driven trial designs in both early stage adjuvant therapy

& advanced stage NSCLC

• Account for inter-patient tumor heterogeneity & genomic

complexity of NSCLC

Target Agent Survival Benefit MMPs Prinomastat, Others No EGFR TKI Gefitinib or Erlotinib No Farnesyl Transferase (RAS) Lonafarnib No PKCα ISIS 3521 No RXR Bexarotene No VEGFR (TKI) Sorafenib No VEGF (Mab) Bevacizumab Yes EGFR (Mab) Panitumumab No TLR9 Agonist PF-351 No EGFR (Mab) Cetuximab Yes** IGFR-1 Figitumumab No VDA ASA-404 No

*In combination with platinum-based chemotherapy versus chemotherapy **EGFR IHC positive

Classic RCT Design (“All Comer”): Phase III Trials of Chemotherapy +/- Targeted Agent* in 1st-line Therapy of Advanced Stage NSCLC

from Gandara et al: Clin Lung Cancer, 2012

Need for a completely “New Way of Thinking” for development of Targeted Drug/Biomarker Combinations: “Master Protocol”

from Gandara et al: Clin Lung Cancer, 2012

Integrated New Drug-New Biomarker Development Paradigm:

Strategies for integrating Biomarkers into Clinical Trial Designs for NSCLC when viewed as a Multitude of Genomic Subsets

Evolution of NSCLC Histologic Subsets  Genomic Subsets

Li, Mack, Kung, Gandara: JCO 2013

Unmet needs addressed by Master Protocol:

• How to develop drugs for

uncommon-rare genotypes?

• How to apply broad-based

screening (NGS)?

• How to achieve acceptable turn-

around times for molecular testing for therapy initiation? (<2 weeks)

• How to expedite the new drug-

biomarker FDA approval process? (companion diagnostic)

Parallel Efforts in “Master Protocol” Design for NSCLC NCI Thoracic Malignancy Steering Committee (TMSC) Task Force

• Early Stage NSCLC

(ALCHEMIST)

• Advanced Stage NSCLC
• Non-Squamous

Friends of Cancer Research (FOCR) Task Force

• Advanced Stage NSCLC
• Squamous (SCCA):

SWOG

• Non-Squamous

SCCA represents an Unmet Need

• All recent new targeted therapies

have been in Adenoca (EGFR/ALK)

• Many new molecular targets have

been found in lung SCCA

• Drugs for each of these targets

Alliance ECOG- Acrin NRG NCI-C SWOG

S1400 Master Protocol Unique Private-Public Partnerships with the NCTN

National Clinical Trials Network S1400 Master Protocol

Vali Papadimitrakopoulou, MD MD Anderson Cancer Center

Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA)

Study Chair: Vali Papadimitrakopoulou, MD UT/MDACC, Dept of Thoracic/Head & Neck Med Oncology Cooperative Groups Co-chairs: Alliance: Everett Vokes, MD ECOG: Suresh Ramalingam, MD NCI Co-Chair: Jack Welch, MD NCIC: Glenwood Goss, MD NRG: Jeff Bradley, MD SWOG: David R. Gandara, MD Steering Committee Co-Chair: Roy S. Herbst, MD, PhD Statistical Co-chair: Mary W. Redman, Ph.D. Molecular Pathology co-Chair: Ignacio Wistuba, MD Correlative Science co-Chair: F Hirsch MD, PhD, P Mack PhD

Rationale for Master Protocol Designs

• NSCLC: multiple and often independent mutations and potential therapeutic

targets.

• Lung SCCA “orphan” group- substantial developments in therapeutics have yet

to be seen.

• Subgroup selection (genotype or phenotype-driven) refined strategy in a

Multi-arm Master Protocol with improved operational efficiency: homogeneous patient populations & consistency in eligibility from arm to arm. Phase II-III design: rapid drug/biomarker testing for detection of “large effects”

• Grouping multiple studies: reduces overall screen failure rate , multi-target

screening by NGS platform: sufficient “hit rate” uninterrupted accrual.

• Bring safe and effective drugs to patients faster, ineffective drugs are replaced

by new improved candidates.

• Designed to allow FDA approval of new therapeutics.

PS Hammerman et al. Nature 000, 1-7 (2012) doi:10.1038/nature11404 Significantly mutated genes in lung SQCC.

Assumptions, Major Elements and Objectives

• Each drug clinical data demonstrating biologic activity in a responsive patient

group against a measurable target, using predictive biomarker assay that has been analytically validated and is suitable for a pivotal trial.

• Squamous cell carcinoma (SCCA), advanced stage, 2nd line therapy
• Multi-arm randomized, controlled phase II/III registration protocol. Each arm
• pens/closes independent of other arms, independently powered for OS.

Positive results at “rolling” interim analysis determine if a protocol arm proceeds to phase III portion.

• Primary Objectives:
• A) Phase II Component: PFS targeted therapy (TT) vs SOC
• B) Phase III Component: OS for TT vs SOC within each biomarker-defined

subgroup.

• Secondary Objectives:

– A) Phase II: Toxicities associated with TT versus SoC. – B) Phase III: a)PFS b) RR and c) toxicities associated with TT versus SoC.

• Exploratory Objectives: A)Additional predictive tumor/blood biomarkers , B)

resistance biomarkers at progression C) tissue/ blood repository from patients with refractory SCCA.

• Organizers: FOCR,NCI-TMSC, FDA, FNIH
• Participants: Entire North American Lung Intergroup

(SWOG, Alliance, ECOG-Acrin, NRG, NCI-Canada)

• Screening: 500-1,000 patients/year
• With 4-6 arms open simultaneously, “hit” rate ~70% in matching a

patient with a drug/biomarker arm.

Interim Endpoint: PFS Primary Endpoint: OS

Genomic Screening

<2 weeks

Randomization Treatment

Assign treatment Arm by marker

NGS/IHC (Foundation Medicine)

Patient Registration Consent Tumor Collection

Investigational Targeted Therapy Standard of Care Therapy

Genomic “Pre-screening” In selected patients

CT* TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib *Archival FFPE tumor, fresh CNB if needed MASTER PROTOCOL Biomarker C TT C+CT CT* Endpoint (Interim PFS) OS Biomarker Β TT B CT* Endpoint (Interim PFS) OS Biomarker A TT A CT* Endpoint (Interim PFS) OS Common Broad Platform CLIA Biomarker Profiling* Biomarker D TT D+E E* Endpoint (Interim PFS) OS Non- match drug Non-match S1400

CT* TT=Targeted therapy, CT=chemotherapy (docetaxel or gemcitabine), E=erlotinib *Archival FFPE tumor, fresh CNB if needed MASTER PROTOCOL Biomarker C FGFRi+CT CT* Endpoint (Interim PFS) OS Biomarker Β Cdk4/6 i CT* Endpoint (Interim PFS) OS Biomarker A PI3Ki CT* Endpoint (Interim PFS) OS Common Broad Platform CLIA Biomarker Profiling* Biomarker D HGFi+E E* Endpoint (Interim PFS) OS Non- match drug Non-match S1400 PI3K M:PIK3CA mut CDK4/6 M:CCND1, Cdk6 ampl, CDKN2 del, mut FGFR M: FGFR ampl, mut, fusion HGF M:c-Met Expr Anti-PD- L1

Statistics

• Phase II component

– Primary outcome: PFS – median null PFS = 3 months – HRpfs = 0.5 (two-fold increase), Power = 90%, 1-sided type I error = 10% – Analysis at 55 progression events – Threshold to continue to phase III: ~ 41% improvement in PFS – RR compared between arms to evaluate if evidence to stop study for early signs of efficacy

• Phase III Design

– Primary outcome: OS – median null OS= 8 months – HRos = 0.67 (50% increase), Power = 90%, 1-sided type I error = 2.5% – Interim analyses at 50% and 75% of expected 256 deaths

• Sample size justification: approximate patient pool in the US 35,800 --

approx 4% clinical trial participation rate → 625-1250 screened/yr → 500-1,000 enrolled/yr

Phase II and III sample size and analysis times

Phase II Component Phase III Design Prevalence N Analysis Time (Months) Total N Analysis Time (Months) 5% 68 34 272 145 10% 80 20 284 81 15% 90 15 296 60 20% 100 12 306 49 25% 104 11 314 43 30% 110 10 324 38 35% 116 9 330 35 40% 124 8 334 33 45% 124 8 340 31 50% 136 7 348 29 55% 136 7 350 28 60% 150 6 354 27

Marker Prevalence Phase II Component Phase III Design @1,000 accrued/ year @500 accrued/ year N Analysis Time (Months) Total N Analysis Time (Months) 2.5% 5% 68 34 272 145 5% 10% 80 20 284 81 7.5% 15% 90 15 296 60 10% 20% 100 12 306 49 12.5% 25% 104 11 314 43 15% 30% 110 10 324 38 17.5% 35% 116 9 330 35 20% 40% 124 8 334 33 22.5% 45% 124 8 340 31 25% 50% 136 7 348 29 27.5% 55% 136 7 350 28 30% 60% 150 6 354 27

LMP: First Patient In (FPI) -- Q1 2014

Study Drug Management

IV III II

Data Management

Trial Starts March 2014

2013 2014 2015 2016

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2

Project Starts January 2013 Initial Meeting March 2013 Drug Selection

Assay Co. Selection

Protocol Development Contracts Approvals

Master IND application

Team Meetings, Teleconferences Other Activities Clinical Operations Management

Master IDE application

Project Management

Pre-Study Activities, Planning

Ann Ashby, MBA Foundation for the NIH

Vince Miller, MD Foundation Medicine

Jeff Abrams, MD Clinical Investigations Branch, NCI

Janet Woodcock, MD CDER, FDA

Mary Redman, PhD Fred Hutchinson Cancer Center